The complex interplay between hormones and the immune system has significant clinical implications. Estrogen has been shown to display a protective role against HIV/SIV transmission, whereas Depot medroxyprogesterone acetate (Depo-Provera), an injectable progesterone based contraceptive is associated with an increased risk of HIV acquisition. Understanding the impact of sex hormones on immune responses and HIV infection will provide insights into the development of a better strategy for HIV prevention. In this thesis, we determined the mechanism underlying estrogen-mediated HIV protection, the impact of Depo-Provera on peripheral and mucosal immune responses and on HIV susceptibility and infectivity in a longitudinal study, and the role of hormonally regulated type I IFN, IFNƒÕ, in HIV infection.

We found that 17ƒÒ-estradiol (E2) protected primary human monocyte derived macrophages (MDMs) but not PBMCs or CD4+ T cells. E2 blocked the step of reverse transcription of the HIV life cycle and induced expression of type I IFNs that contributed to HIV protection. In the longitudinal study, we analyzed the expression of immune markers for HIV preference (integrin ƒÑ4ƒÒ7, CCR5 and CD38) on peripheral and cervical cells (cytobrush) and the levels of immune mediators in vaginal and cervical secretions in women before (visit 1), one month (visit 2) and 3 months after Depo-Provera injection. We found that Depo-Provera altered the immune profile of peripheral CD4+ T cells and increases their susceptibility to HIV infection ex vivo. These effects differed between women of different ethnicities. After receiving Depo-Provera, women had higher degrees of HIV infectivity but lower levels of immune mediators in cervical secretions.

Like E2, IFNƒÕ exhibited a potent anti-viral activity in MDMs but a moderate inhibitory effect on PBMCs and activated CD4+ T cells. IFNƒÕ down-regulated cell surface expression of the co-receptor CCR5 but not CD4 or the co-receptor CXCR4. IFNƒÕ blocked intracellular steps of HIV reverse transcription and nuclear import. IFNƒÕ-stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFNƒÑ in macrophages. The protection did not appear to operate through known type I IFN-induced HIV host restriction factors such as APOBEC3A and SAMHD1. IFNƒÕ induced significant phagocytosis and reactive oxygen species, which contributed to the block to HIV replication. These findings offer insights into the impact of sex hormones on immune modulation and HIV infection in vitro and ex vivo. Understanding underlying mechanisms of hormones on innate immunity and the subsequent effect on HIV infection has implications for HIV prevention.